Nitric oxide synthases are crucially involved in the development of the severe cardiomyopathy of caveolin-1 knockout mice.
Targeted ablation of caveolin-1 (cav-1) results in a severe cardiomyopathy. How the loss of cav-1 mediates these abnormalities is currently under investigation. Mounting evidence indicates that cav-1 acts as a negative regulator of endothelial nitric oxide synthase resulting in a constitutive hyperactivation of the nitric oxide (NO)-pathway in cav-1 knockout mice (cav-1 ko). In this context we hypothesized that disturbed NO signalling is implicated in these changes. To explore this question cav-1 ko were compared with knockout counterparts experiencing 2 month postnatal NO synthase inhibition by N(G)-nitro-l-arginine methyl ester (l-NAME) treatment. Chronic l-NAME treatment resulted in significant improvements in heart function and exercise capacity in cav-1 ko. Furthermore, we found evidence for an enhanced radical stress in hearts of cav-1 ko which was markedly reduced by l-NAME treatment. Collectively, these findings suggest that NO synthases play a crucial role in the evolution of heart failure evident in cav-1 ko.
Wunderlich
Carsten
C
University of Technology Dresden, Department of Medicine and Cardiology, Medical Clinic, Fetscherstr. 76, Dresden 01307, Germany. carstenwunderlich@gmx.de
Schober
Kristin
K
Kasper
Michael
M
Heerwagen
Christian
C
Marquetant
Rainer
R
Ebner
Bernd
B
Forkmann
Matthias
M
Schoen
Steffen
S
Braun-Dullaeus
Ruediger C
RC
Schmeisser
Alexander
A
Strasser
Ruth H
RH
D000818:Animals; D009202:Cardiomyopathies / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D051242:Caveolin 1 / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005355:Fibrosis; D051379:Mice; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010805:Physical Conditioning, Animal; D013481:Superoxides / Q000378:metabolism
D051242:Caveolin 1; D004791:Enzyme Inhibitors; D013481:Superoxides; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D019331:NG-Nitroarginine Methyl Ester